This application claims priority to the Swedish Application entitled “A Novel Engineered Superantigen for Human Therapy”, filing No. 0102327-4 filed Jun. 28, 2001, which is incorporated herein by reference in its entirety.
1. Field of the Invention
The present invention relates to the field of immunology and proliferative diseases, such as cancer. More particularly, it relates to compositions and methods of use, wherein the compositions comprise superantigens that have been modified to reduce seroreactivity.
2. Related Art
Superantigens (SAg's) constitute a group of bacterial and viral proteins that are extremely efficient in activating a large fraction of the T-cell population. Superantigens bind directly to the major histocompatibility complex (MHC) without being processed. In fact, the superantigens bind unprocessed outside the antigen-binding groove on the MHC class II molecules, thereby avoiding most of the polymorphism in the conventional peptide-binding site. The mechanism of binding depends on the superantigen binding to the T-cell receptor (TCR) in the Vβ chain, instead of binding to the hypervariable loops of the T-cell receptor (TCR).
Staphylococcal enterotoxins (SEs) are a homologous group of superantigens, with regard to both structure and function (Papageorgiou et al., 2000). They are known to be the major cause of food poisoning and toxic shock syndrome in humans.
A novel SAg-based tumor therapeutic approach has been developed for the adjuvant treatment of solid tumors. It utilizes both main arms of the immune system by incorporating the Fab part of a tumor-specific monoclonal antibody and a T-cell activating SAg in a single recombinant fusion protein. Fab-SAg proteins bound to tumor cells can trigger SAg-activated cytotoxic T-cells to kill the tumor cells directly by superantigen antibody-dependent cell mediated cytotoxicity, SADCC. In addition, activated T-cells produce tumoricidal and pro-inflammatory cytokines counteracting the problems of tumor heterogeneity, and macromolecular uptake, respectively.
Superantigen-based tumor therapeutics have had some success, however, one clinical problem that needs to be addressed is the activation of the systemic immune system. Fusion proteins with wildtype SEA have been investigated in clinical trials of colorectal and pancreatic cancer (Alpaugh et al., 1998). Even though encouraging results were obtained, limitations have been observed. Firstly, the product was very toxic. Secondly, preformed antibodies against the superantigens in the patients made the dosing complex. In addition, the product was immunogenic. Therefore repeated cycles of therapy was only possible in a limited number of patients.
Until the present invention, SAg-based therapies were dose-limiting. The present invention is the first to modify a superantigen resulting in decreased seroreactivity with retained superantigen activity; thus, the present invention is novel and non-obvious.